 Welcome, everyone. I believe I'm the first talk of the day for thanks. Thanks for coming out bright and early a lively crowd I see Everyone went to bed real early last night. No after parties. I assume so Kudos to all of you. So I'm really excited to be here. This is my first time in Finland And I'm excited to share a little bit about this technology called CRISPR That we're using at mammoth in particular to build genetic therapies So well, we'll start by going a little bit into what CRISPR is And then we'll go into kind of what we're doing at mammoths to take this technology to the next step so If you haven't heard of CRISPR CRISPR is this really exciting new genetic engineering technology And it was the first papers were published about 10 years ago And one of my co-founders Jennifer Doudna actually won the Nobel Prize for her pioneering work in this technology a couple years ago And what's really exciting about this technology is that it's a way of Programming life very similar to how we program computers And if you remember your high school biology, at least this is how I was taught biology Biology is taught as this very kind of squishy messy like kind of intractable field of study that's almost like a stamp collecting things the famous Ernst Rutherford quote and This technology is a way of really enabling us to engineer biology in very reproducible and very specific ways And I think that's incredibly exciting because there's no more complex computer than ourselves right in our brains You know neural nets and all these things are all trying to mirror our brains in some way and CRISPR is a really reproducible and very specific way of actually changing the code of life so DNA or RNA that's in all of ourselves So when the technology first came out I put a bunch of magazine covers here of kind of the things that people were talking about So it's like editing humanity engineering the human race And if you really think about the long term of like okay, we can edit our genomes and what that can mean There's all sorts of different directions you can go and it doesn't even have to be therapeutics You can think about agriculture and engineering plants so that we can have better crops and more nutritious meals Or you can think about Diagnostics or you can think about my buy a manufacturer. I've seen some other companies here They're trying to leverage like microbes and other organisms to manufacture products that we use in a variety of things And these can all be super charged with the technology like CRISPR that allows you to actually engineer these organisms But the area that I'm most excited about is definitely Therapies and in specific and specifically genetic therapies So if you think about our genome as a giant word document So it's billions of letters in this case ATC and G. It's very limited alphabet So maybe a simpler language in some ways than what you would actually find in a word document, but You can think of CRISPR as two components the first component and they're equally important The first component is a control F are kind of like a Google search engine So if you have this giant word document of like billions of base pairs and you only want to Change a very specific word in that document or maybe even a specific letter or maybe a paragraph The first step is you have to somehow find it and that's a really really difficult problem And remember we're dealing in messy biology space as well So this CRISPR technology can actually go in and locate a very specific part of the genome And then the next thing is that you want to somehow change it, right? So if you just locate it, that's fine That's that's a good first step but you need to actually be able to modify it and you can think of that as like kind of a control X or a Copy-paste and as it turns out there's different flavors of this CRISPR technology Some of them that can like even italicize a word or bold it or delete a word or add a paragraph And depending on what you're trying to do you might want to leverage any or all of these different techniques But before we dive into that I think it's useful to take a step back in time a little bit It's like what CRISPR is Could it's anyone in the audience actually knows what CRISPR stands for it's an acronym I don't know if it's too early for a call in response So someone wants to throw out what it means but it stands for clustered regulatory interspace short palindroma refeeds It's a bit of a mouthful you can see why we call it CRISPR And the what it comes from is actually this really interesting Natural phenomenon which is that bacteria very similar to ourselves have an adaptive immune system So our bodies try and prevent us from being sick as it turns out bacteria even though they're these very simple relative to us Organisms they also have an adaptive immunity and that adaptive immunity is CRISPR and what they're trying to protect themselves against is Viruses that are invading them. So again, if you remember your high school biology Viruses will invade a bacteria inject a bunch of genetic material in order to make that bacteria a virus factory That then will create a bunch of viruses and kill the bacteria. So bacteria don't like that understandably and The way it works is that if a virus Finds a bacteria and it injects its genetic materials. This is like say DNA or RNA Then what happens is that the bacteria is constantly having these CRISPR proteins so CRISPR is a protein going around And it has what's called a guide RNA and that's the the thing in red with the little herringbone black Cartoon next to it and what this guide RNA does through a process We won't get in today is that it basically says I've been Invaded by viruses before and my billions of progeny before me have been invaded by viruses before So I know the red sequence is bad That's a viral sequence and it's not found in my own genome or in other stuff that I don't care about So if you see that red sequence cut it up Physically just chop it up and if you chop up genetic material, it's rather useless at least for this purpose So these CRISPR proteins are kind of little sentinels that are in the bacteria going around saying have I been Invaded by a virus and if so I'm going to defend myself by chopping it up with molecular scissors They're just physically cleave the the DNA And if we zoom in on that so this kind of gray Glob here is the what we call cast system We're the most famous one being the thing called cast 9 that you might have heard of if you've read about the space And then that again the red thing is the guide RNA And that's really the secret sauce of CRISPR is that you can use the same cast 9 cast protein for everything But you can switch out that guide to go after any sequence and that's the kind of programmable part So if you think of the CRISPR cast system as Google then the guide RNA is kind of what you're typing into Google to search for something And as it turns out, we're really really good at Synthesizing these guides and we can also come up with rules for designing them So this is a very facile process and it's not it's very democratizing actually There's other technologies before CRISPR that could be used for types of genetic editing But one of the main pitfalls of them is that they were very laborious to actually get to work you would take, you know multiple PhDs like years to actually develop The tool for a specific application whereas this literally high schoolers can do this which is Incredibly exciting. I think and really kind of like opens up the the doors to a whole new world of biology There's another famous quote about Science moves forward with new tool development. I think this is a really clear example of that as well It just opens up the possibilities of what kind of experiments you can even think about And if you remember your high school biology again, I promise the last time I'm going to say that then you have your base pairing a to T C to G so your guide RNA the way it can tell What sequence you're going after is that it's complementary to the sequence that you're going to and again? That's a very easy thing to design So that's the CRISPR cast system. So it's an incredibly exciting technology But there are real limitations to this kind of first generation of it and at mammoth That's what we're kind of driving forward is this next generation that we think overcomes some of these limitations where some of the key Limitations here that we'll talk about are in particular Barriers to what we call in vivo applications. We'll go into that second sets in the body Some of the other things people worry about are things like off target effects So what if it's not only going to the sequence you want it to go to you? What if in that billions of base pairs in that word document? It's actually going a couple other places that could be pretty bad. You don't want to go into other locations And you can think about can you actually target every region of the genome and a bunch of other things as well? But before going too much into the limitations I do want to say that the the first generation technologies like cast 9 have made immense progress So actually in the last month the very first CRISPR based therapy was approved for the first time in the world in the UK and very likely there'll be news in the US in the next month as well and Apologies to everyone from software in the room But ten years from a fundamental discovery to something actually being approved by the FDA is incredible That's a testament to the technology It's a testament to the teams and companies and academic labs around the world that have been driving this forward But that is incredibly fast and it's incredibly effective as well So I want to point out this is this is sci-fi But it's not sci-fi this is something where there's people walking around today who have been treated with this technology And I think that's incredible. So it's more about how do we take it to the next level and in particular at mammoth What we're really excited about is you can use this to actually potentially cure diseases So when we think about drugs today, we really think about it as like, you know, you're on it the rest of your life It's it's treating the symptoms often or it's it's not actually curing you though of the disease and for diseases that have a genetic basis for example like sickle cell disease or like beta thalassemia or you know many other Disorders you can think of like Alzheimer's for many patients These have a very clear location in the genome sometimes that we've known for decades that if you can change that location in the genome You can cure the disease functionally potentially and that's very very exciting But there's two ways you can do this the first one is called in vivo and that's in the body And the second one is ex vivo are outside the body and ex vivo Means you take the cells out and you edit them outside the body and then you put them back in So you can imagine for like blood-based disorders like sickle cell disease This is very effective and that this gives you a lot of latitude you can do a lot of things to cells outside of the body Whereas for in vivo That means you're giving an injection. It's going to the tissue and it's actually editing in the body So if you can do everything ex vivo, that'd be great It's a lot of advantages But as it turns out many of the diseases that we care about that are genetic Maybe I would dare say the majority are not things where you can take the cells out of the body Like if I take your brain out and then put it back in there's gonna be side effects I imagine so you want to be able to somehow inject it have it go where it needs to go and This means you have to worry a lot about like are you doing it effectively? Are you doing it safely and one of the biggest things you have to worry about is the delivery of the system and Before going to deliver a I want to point out that all the all the work We're doing is only possible because the really great team that we have including my co-founders Janice Lucas And of course Jennifer Doudna who won the Debel prize for her work in this space And and we have a really great set of investors that believe in the long-term vision of building a biotech company that can actually tackle these grand challenges and The way we kind of tackled this delivery problem is that actually one of the big limitations is that these proteins are really large And if you think about proteins, they're all small relative to us But if you zoom down onto their scale, they actually vary in size quite a bit And one of the things we realized is that because CRISPR systems are the adaptive immunity of bacteria There's billions of bacteria all around us and if we go out and sample it it could be from farms It could be from like toilet seats that can be from anywhere bacteria all around us Then there's gonna be all sorts of potential new CRISPR technologies So over here you can see on the left We we sampled all these different sites and like digested all these different databases And we sort through billions and billions of proteins to find new versions of this CRISPR technology that have new names Like cast fee or cast 14 that are not cast 9 and one of the big Things that we're excited about is that actually we found that some of these are much much much smaller And there's other advantages as well that we won't go into today, but on the size This actually ends up being incredibly important So on the bottom of this slide are what we call the legacy systems So these are things like cast 9 which is one we were kind of talking about at the beginning And they're around let's say 1400 amino acids. So they're quite a large size and If you kind of mind through all these metagenomic Databases what you can find is actually what we call these ultra compact systems that are a third or less the size of the legacy ones You can see them up here in green and what's really interesting about this is if you look at how we actually deliver these to the different Parts of the body. There's two dominant ways the first one You may have heard of because it's used in the vaccines so that's LMP or lipid nanoparticle And that's really useful in particular for going to certain tissues like the liver But if you want to go extra hepatically so anywhere that's not the liver You really typically are going to use this thing called AV and this is another really interesting story About kind of co-opting natural machinery in this case adeno associated viruses again viruses are really good at getting them to Cells and using it to actually deliver our own payloads But the big limitation is that it can only fit certain sizes and the best analogy is probably like let's say you're in Downtown Helsinki and you're trying to get around it's gonna be a lot easier if you have a smart car versus like a freight trailer Right, it's just gonna be more difficult to get to the different areas But if you your cargo requires a freight trailer you got to use the freight trailer But if you had a smart car you could more easily and effectively probably safely get to where you need to go And and that's the advantage of these really small systems So they can really squeeze into these things like AV with a bunch of room for doing doing other other applications as well and And the main other application that we're really excited about that this really enables Goes back to the one of the things I mentioned at the beginning that there's different types of edits You might want to do to that word document, so you can imagine Instead of just turning a gene off completely or just turning it on completely Maybe you want to adjust the volume of it So maybe you want to bold or italicize the word to abuse the metaphor and that could be like epigenetic editing So instead of even changing the the DNA itself Maybe you just add some methylation or something that modifies the expression Or maybe you want to add in a whole new paragraph Maybe you want to just add a whole new sequence That would be something like gene writing or maybe out of those billions and billions of base pairs You want to change a single letter and that would be like base editing for example And these are all different techniques that kind of use the CRISPR system as that search function And they have a different instead of copy-paste. They're doing something something different And depending on and this is really going to be driven by the disease that you're going after what type of edit You want to do it can vary quite a bit So what you're able to do by having these really small systems is that you can now deliver all this other payload You need to do it to do these unique types of edits and these payloads can be quite large as well And this has been a really really big challenge of the space But I think if we really want to deliver on the promise of genetic medicine You need to be able to do any type of edit anywhere. That's really the goal that we have to achieve So this clicker works I think the key things I'd like you to take away from today aside from some biology. Hopefully Are our two-fold so one we're at this incredible Crossroads in biology in general where it really is becoming more of an engineering discipline And we're really able to think about it kind of more in that fashion And that's definitely not how I was taught biology And I think it really opens up a lot of different doors to a lot of exciting applications in Therapeutics and beyond and then the second one which is more more specific to kind of mammoth as a company is that these Engineering applications allow you to build what we call platform companies and these have been very rare in biology often It's like the first drug you build great you you're actually successful the second one's just as hard the third one's just as hard But when you have a technology like CRISPR because it's Reprogrammable building the second third fourth drug on top of it actually gets easier and easier and this is not something That's typical in biology It's this new kind of wave of what we call platform biotech And we're very excited that mammoth is a part of this wave and it really enables you to actually build lasting biotech companies That don't just go after one disease or two diseases But actually build out whole platforms that can tackle potentially all of genetic disease and that's not something that's been possible before So that's what I'd like you to take away from today. Thanks for coming out bright and early and hope to see you round If you have any questions. Thanks everyone